Sensory transduction
Sensory neurons must reliably detect and amplify the weakest stimuli, yet remain functional at the highest intensities. To do this, they combine a polarized cell structure with sophisticated signaling cascades and ion dynamics. A central question in sensory physiology is how the stimulus, cellular geometry, ionic environment and signal transduction pathway together determine the neuronal response. Experimental limitations make it hard to observe molecular processes in tiny compartments such as the outer segment of photoreceptors or the cilia of olfactory receptor neurons.
I combine electrophysiology to record responses, biophysical modeling to understand molecular processes, mathematics for analysis and quantification, and computer simulations that capture the complexity and predict the neuronal response. Following a bottom-up approach, I derive the response of photoreceptors and olfactory receptor neurons from the underlying biology, and develop computer tools to simulate neurons in normal and pathological conditions.
More on phototransduction and olfaction →
Transcription factor search
Cellular responses require fast activation or repression of specific genes, which depends on transcription factors (TFs) quickly finding their promoters within a large genome. TFs alternate between bulk diffusion and sliding along the DNA (facilitated diffusion). Using mean first passage time (MFPT) analysis, I study a framework that switches between a bulk mode and two sliding modes triggered by conformational changes: a search mode with fast, unspecific sliding along the DNA backbone, and a recognition mode with specific, strong binding and slow displacement. We derived exact expressions for the MFPT to bind the promoter, and for the probability of binding before detaching when arriving at the promoter site.
Narrow escape theory
Diffusion is a key regulator of the forward rate of chemical interactions. Many cellular processes depend on the rate at which diffusing molecules meet each other or find a small target. When few molecules are involved, the time to reach a small target in a confined micro-environment is often the limiting step, and it depends strongly on the geometry of the microdomain. Narrow escape theory, pioneered by D. Holcman, determines how geometry and other diffusional properties affect the encounter rate between a diffusing ligand and its target.
